When the smoke gets in your enzymes
Caffeine as a gateway drug, part five
This is part five in our caffeine as a gateway drug series where we learn about how drugs work by exploring caffeine and using plain language.
So far, we’ve considered how drugs get into the body, move around in the bloodstream and exert actions by interacting with receptors.
Now we’re going to look at the first stage of clearing drugs from the body, courtesy of the liver.
Those of you who’ve been paying attention will notice some foreshadowing of the liver’s role in part two, where we talked about the first pass metabolism that happens after drugs are administered into the gut.
Now we’re going to focus on the actions of the liver exclusively.
I’ve never been a smoker. Even as a teen, when peer group pressure was peaking, I never even had a puff.
It’s not because I was worried about getting lung cancer. It’s not because I was afraid of breaking the rules.
It was entirely down to vanity.
Yes, it seems my fear of developing yellow teeth outweighed any of the perceived benefits. I was known for my smile and I wasn’t about to mess with that.
I consider this a near miss. Because I’m pretty sure if I ever started I’d have had a terrible time trying to quit.
Nicotine is an extremely addictive substance, so most people find it hard to quit. But in addition to the drug itself being addictive, I’m the sort of person who loves taking up new habits.
The best method I’ve found to break a bad habit is to replace it with one that isn’t quite as bad.
Habitually hitting up the vending machine at 3pm for a chocolate bar? Swap it out for a chocolate flavoured high protein up and go drink.
Habitually doomscrolling while waiting for my son to fall asleep? Swap it out for writing a Substack newsletter.
Yes, I have no doubt that if I started smoking cigarettes I’d have been habituated in no time at all.
One of the methods I might’ve tried to sub in as a not so bad alternative would be to up my coffee intake to compensate for my lack of nicotine.
After a couple of days of experiencing the jitters, I might’ve had enough. I’d probably re-start smoking and the jitters would subside, confirming my hypothesis that quitting is more trouble than it’s worth.
The trouble with this is, I’d be wrong.
Yes, the absence of smoking might’ve resulted in me getting the jitters, but nicotine withdrawal may not be the sole cause. To understand the cause we need to look at the other drug in play…our friend caffeine.
I want you to picture the scene of a supermarket with a bunch of shoppers pushing around trolleys laden with various groceries.
This isn’t a very modern store. Each checkout lane is numbered, with human operators who are quick to let you know whether or not they’ll accept you in their lane based on the contents of your trolley.
You’ve only got a slab of coke cans? Head to the fast service counter please. Your trolley contains hair products? Even numbered lanes only for you. You’ve got alcohol? Sorry ma’am, you’ll have to go to lane number 9 and wait your turn.
The pace of the lanes is pretty steady, meaning the groceries get repackaged into bags ready for transport home at a pretty even pace most of the time.
After you watch this scene for a while you start to notice something. When a checkout operator returns from their rest break, the pace of groceries moving through their checkout changes.
Some checkouts move faster, as though the cashier has been energised, getting the groceries packed up and cleared out of the lane quick smart.
Others have turned into sloths, moving in slow motion. There starts to get a backlog of shoppers stuck in the supermarket because of this.
A few seem to be immune to the effects of the break period, maintaining a consistent work pace throughout the observation period.
This shopping scene is an analogy of what happens in your liver during drug metabolism.
The liver and its metabolising enzymes
The purpose of drug metabolism is to repackage the substances circulating in your bloodstream into compounds that can be excreted by the kidneys. Like repacking the contents of your trolley into shopping bags so you can easily put them in the boot of your car to drive home.
The different lanes and their respective operators represent the various enzymes within the liver. This is what does the work of breaking down the drug molecules into different components that can move into the urine.
The story of the cashiers only letting certain trolleys of groceries allowed into their lanes is to illustrate how certain drugs are processed by particular enzymes. Some drugs may be broken down by a range of enzymes, others by something specific.
There are lots of different enzymes that metabolise drugs, but two groups that are useful to know about if you use drugs are alcohol dehydrogenase and the cytochrome p450 (CYP450) enzymes.
Alcohol dehydrogenase (and aldehyde dehydrogenase) is responsible for breaking down ethanol contained in alcoholic beverages. The CYP450 enzymes are a family of enzymes that break down a whole heap of drugs.
Our genes influence how many of these enzymes we each have in our bodies. Some people naturally have more, others less. This is why some drug information may suggest different dosing for specific ethnic groups, because there’s known to be variations in how they metabolise a particular drug. It’s also one of the reasons why some people of particular ethnicity are less able to tolerate alcohol.
The genes might determine how many liver enzymes we start out with, but environmental factors influence how well these enzymes perform over time.
If we go back to the supermarket analogy, this relates to how the cashier’s were affected by having a break and getting something to eat and drink. Some go faster, some slower, and some are unchanged.
The same thing can be seen with the function of our liver enzymes which are impacted by the substances we consume.
Some substances make certain enzymes work faster, which we call induction. Just as this gets trolleys full of groceries packed up ready to get out of the store more quickly, so too does it break down the drug compound faster. This means there is less drug circulating in the bloodstream and able to exert its effect.
Other drugs slow the enzymes down, which is called inhibition. Just as the sloth like movement of the cashiers resulted in a backlog of trolleys, so too does enzyme inhibition result in an increased amount of certain drugs circulating in the bloodstream for longer.
This is the basis of what we call pharmacokinetic drug interactions.
To understand this better, let’s return to our story about caffeine and the cigarette smoking. The picture below might give you a hint about what’s going on here.
The main way that caffeine is cleared from the body is by a CYP450 enzymes called CYP1A2. This is an enzyme that is influenced by environmental factors.
One of the substances that makes CYP1A2 work faster is cigarette smoke. This means smoking results in caffeine being cleared out of your system more rapidly than usual. Because of this, you’ll get less effect from a cup of coffee than if you weren’t smoking.
Now, if you’re a regular smoker you might not notice this much. The stimulant action of the nicotine may compensate for the reduced caffeine effect.
When you stop smoking something different happens. The CYP1A2 enzyme slows back down, meaning you’ll now have a higher amount of caffeine in your body after that same cup of coffee.
If you’re like me and try to replace a bad habit with something not so bad and increase your coffee consumption to help the quitting process, you could find yourself with much higher levels of caffeine circulating in your bloodstream than what you’re used to.
As we covered in earlier posts, higher amounts of drug in the bloodstream increase adverse effects. And one such adverse effect for caffeine is feeling anxious and getting the jitters. Symptoms that can easily be mistaken for nicotine withdrawal, and a good reason to resume smoking.
The lesson here if you’re a smoker is to watch your caffeine intake when you decide to quit, even if you use nicotine replacement products.
And if you’re taking other drugs, including herbal products, supplements, over the counter and prescription medicines, it’s a good idea to find out if they are involved in these types of drug-drug interactions. This is particularly important if you are stopping or starting something because that’s when things can really get thrown out of whack. Check with your pharmacist or doctor if you’re unsure or want to know more.
If you’d like to go on a deeper dive into CYP450 enzymes, check out this post:
Well, that's interesting! I quit smoking in 2002 so it's starting to get a little fuzzy, but I remember that coffee did seem to hit a lot harder without the smokes.
One thing I do recall quite clearly is getting dumber after quitting smoking. My memory dropped, I had a hard time memorizing or focussing on things at work. I seemed to think slower for months. It was quite a while before I felt normal.